7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin is known as Irinotecan and has the structure represented in Formula (I). The drug is available in the hydrochloride trihydrate form of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin herein after referred to as CPT-11.

7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin is a camptothecin derivative that is highly active against lung and colorectal cancer and has been used for treating several types of tumors. It is sold in the form of the hydrochloride trihydrate salt (CPT-11) under the trade name CAMPTOSAR.
CPT-11 has shown activity against a variety of tumor types, particularly refractory colorectal tumors, and is used for the treatment of various forms of cancer. Its primary use is in the treatment of colon cancer, particularly advanced colon cancer. It is also of interest for treatment of other cancers, such as cancers of the lung, the stomach and the pancreas.
The compound of formula (I) was first disclosed in U.S. Pat. No. 4,604,463 which, describes a broad family of camptothecin derivatives including formula (I), its pharmaceutically acceptable salts and preparation thereof. The same patent also describes a process for the preparation of compound of formula (I) comprising condensation of 7-ethyl-10-hydroxy camptothecin with 1-chlorocarbonyl-4-piperidinopiperidine in presence of pyridine at room temperature.
Compound of formula (I) is usually prepared semi synthetically from natural camptothecin, which occurs in a Chinese tree, Camptotheca acuminata. Sawada et al., Chem. Pharm. Bull. Vol. 39, No. 6, 1446-54 (1991), describes the preparation of compound of formula (I) and crystal structure of its hydrochloride trihydrate (also known as CPT-11) that is currently used for the manufacturing of the commercially available product). Crystalline form of CPT-11 as described by Sawada et al. is herein after referred to, for convenience, as “Form b”. It is also characterized by PXRD peaks at about 7.60, 8.30, 9.55, 11.0 and 12.40°±0.2 degrees 2θ.
In the reference cited above, the method of preparation of the compound formula (I) from natural camptothecin involves five chemical steps and subsequently the base is converted to the HCl salt. This method suffered from very low yield (20%). Hence, there is a need in the art to develop a simple and efficient process for the bulk production of compound of formula (I).
WO2006084941 discloses process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts. This process involves elimination of [1,4′]-bipiperidinyl-1′-carbonyl chloride by adding suitable amine after completion of the reaction.
Polymorphism, the occurrence of different solid-state forms, is a property of many molecules and molecular complexes. A single molecular entity may give rise to a variety of solid state forms having distinct crystal structures and physical properties such as melting point, powder X-ray diffraction pattern, infrared (IR) absorption fingerprint and different physicochemical properties. One solid-state form may give rise to several polymorphic forms, which are different from one another in all the above properties.
WO2003074527 disclosed a polymorphic form of crystalline hydrochloride salt of formula (I) characterized by PXRD peaks at about 9.15, 10.00, 11.80, 12.20, 13.00 and 13.4°+0.2 degrees 2θ.
WO2007035709 disclosed four polymorphic forms of crystalline hydrochloride salt of formula (I) characterized by powder X-ray diffraction peak value as depicted in below Table 1.
TABLE 1Form IForm IIForm IIIForm IV12.3420.3923.969.1924.7922.2920.929.9810.9412.0721.0818.898.208.4821.0915.2727.6711.8323.8316.1622.7215.7524.3225.7421.2318.5210.2827.06
WO2008148260 disclosed a polymorphic form of crystalline hydrochloride salt of formula (I) characterized by PXRD peaks at about 7.80, 9.96, 13.28, 15.62, 19.98, 20.36, 22.34, 22.66 and 30.18°±0.2 degrees 2θ.
Though several processes for preparing both the compound formula (I) as well as its hydrochloride salt are known, only few are environmental friendly and economically viable processes for the preparation of highly pure CPT-11. Further, in most of the prior art references, the [1,4′]-bipiperidinyl-1′-carbonyl chloride (II) has been stated to be unstable and therefore the preparation of compound of formula (I) is normally carried out through the formation of the HCl salt of (II). We have surprisingly found that [1,4′]-bipiperidinyl-1′-carbonyl chloride prepared according to the process of the present invention is stable and can be isolated. We herein therefore disclose the stable form of [1,4′]-bipiperidinyl-1′-carbonyl chloride (II). The use of the stable form reduces the formation of the impurities and also substantially increases the yield of the final compound (I).
We herein disclose improved process for the preparation of the compound of formula (I) and also process for the preparation of the hydrochloride salt of compound formula (I) prepared according to the process of the present invention. The process being environmental friendly and economically viable, for the preparation of highly pure CPT-11. We herein also disclose a new impurity of CPT-11, process of preparation of these impurities, which may be used as reference standards.
In order to obtain marketing approval for a new drug product, manufacturers must submit to the regulatory authority evidence that the product is acceptable for administration to humans. Such a submission must include impurity profile of the product to demonstrate that the impurities are either absent, or present in a negligible amount. Different regulatory authorities have promulgated guidelines requiring applicants to identify the impurities present in the product and also disclose their concentration in the product. They also provide the maximum level of impurities allowable in the product. Thus for e.g. USFDA recommends that drug applicants identify all the impurities having concentration of 0.1% or greater in the active ingredient. Therefore, there is a need to check impurity profile and identify the impurities and also their concentration in the active ingredient.
The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the CPT-11 contained in the product mixture into an active pharmaceutical ingredient, it must be analyzed for purity, typically by HPLC or GC analysis.
Generally, impurities (side products, byproducts and adjunct reagents) are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram. Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as “retention time”. This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of some reference marker. Thus, it is sometimes desirable to select an alternative compound that is added to, or is present in, the mixture in an amount significant enough to be detectable and sufficiently low as not to saturate the column and to use that as the reference marker. Researchers and developers in drug manufacturing understand that a compound in a relatively pure state can be used as a reference standard” (a “reference marker is similar to a reference standard but it is used for qualitative analysis) to quantify the amount of the compound in an unknown mixture. When the compound is used as an “external standard” a solution of a known concentration of the compound is analyzed by the same technique as the unknown mixture.
The reference standard compound also can be used to quantify the amount of another compound in mixture if the “response factor”, which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined.
The reference standard compound can even be used as an internal standard when the unknown mixture contains some of the reference standard compound by using a technique called “standard addition” wherein at least two samples are prepared by adding known and differing amounts of the internal standard. The proportion of detector response due to the reference standard compound that is originally in the mixture can be determined by extrapolation of a plot of detector response versus the amount of the reference standard compound that was added to each of the sample to zero.